Hepatitis C, originally called non-A, non-B hepatitis, was first described in 1975 as a disease serologically distinct from hepatitis A and hepatitis B (Feinstone, S. M. et al. (1975) N. Engl. J. Med., 292:767-770). Although hepatitis C remains the leading type of transfusion-associated hepatitis as well as an important part of community-acquired hepatitis, little progress was made in understanding the disease until the identification of hepatitis C virus (HCV) as the causative agent of hepatitis C via the cloning and sequencing of the HCV genome (Choo, A. L. et al. (1989) Science, 288:359-362). From the sequence information generated by this study, HCV was characterized as a small, enveloped, positive-stranded RNA virus.
HCV is a major cause of both acute and chronic hepatitis worldwide (Weiner, A. J. et al. (1990) Lancet, 335:1-3). Approximately 80% of individuals acutely infected with HCV become chronically infected and more than 20% of these individuals eventually develop liver cirrhosis (Alter, H. J. Seeff, L. B.: Transfusion Associated Hepatitis, In: Zuckerman, A. J. Thomas, H. C. (eds): Viral Hepatitis: Scientific Basis and Clinical Management, Edinburgh Churchill Livingstone, 1993). In a vast majority of infected individuals, HCV causes a chronic disease leading to loss of liver function, and, without a liver transplant, ultimately to death. Post-transplant patients are still at risk from re-infection of the new liver from circulating HCV. In addition, a strong association has been found between HCV infection and the development of hepatocellular carcinoma (Bukh et al. (1993) Proc. Natl. Acad. Sci. USA, 90:1848-1851). HCV infection also seems to be associated with other diseases, including some autoimmune diseases (Manns, M. P. (1993) Intervirol., 35:108-115; Lionel, F. (1994) Gastroenterology. 107:1550-1555). Thus, significant morbidity and mortality is caused by HCV infection worldwide. Presently, there is no immunoprophylaxis or immunotherapy to prevent and/or treat HCV infection and in addition, current drug therapies are only partially effective. Therefore development of an effective immunoprophylaxis or immunotherapy is of high priority.
The hepatitis C virus contains three putative structural proteins, consisting of the N-terminal nucleocapsid protein (termed “core”) and two envelope glycoproteins, “E1” and “E2”. (See, Houghton et al. (1991) Hepatology, 14:381-388).
The HCV E1 and E2 proteins are of considerable interest in immunoprophylactic and immunotherapy development. Indeed, recombinant vaccines based on these molecules have been shown to be protective against experimental challenge with HCV in primate studies. Specifically, Choo et al. ((1994) Proc. Natl. Acad. Sci. USA, 91:1294-98), using recombinant E1 and E2 proteins of HCV-1 as immunogens, reported the successful vaccination of chimpanzees against challenge with the homologous strain of HCV. However, Choo et al. did not demonstrate protection against challenge with a heterologous strain of HCV and the discovery of the extraordinary diversity of HCV genomes based on sequence analysis of numerous HCV isolates (Bukh et al.; Proc. Natl. Acad. Sci. USA, (1993) 90:8234-8238, Bukh et al. (1994) Proc. Natl. Acad. Sci. USA, 91:8239-8243) suggests that a successful vaccine must protect against challenge by multiple strains of HCV. This conclusion is supported by the work of both Farci et al. (Farci, P. et al. (1992) Science, 258:135-140) and Prince et al. (Prince, A. M. et al. (1992) J. Infect. Dis., 165:438-443), each of whom presented evidence that while infection with one strain of HCV modifies the degree of the hepatitis C associated with the reinfection, it does not protect against reinfection with a closely related strain.
Since antibodies elicited to HCV may neutralize the infectivity of the virus (Shimizu et al. (1994) J. Virol., 68:1494-1500; Farci et al. (1994) Proc. Natl. Acad. Sci. USA, 91:7792-96), the administration of a highly reactive, neutralizing anti-HCV antibody preparation to an individual who is at risk of infection, or who has recently been exposed to the infectious agent, may provide passive immunity to the immunized individual.
Thus, there is a need for antibodies directed against HCV which may be used for protecting individuals who are at high risk from HCV infection, or who have recently been exposed to HCV. Preferably, the neutralizing antibodies would be broadly cross-reactive against different HCV strains.